Although Hodgkin's Lymphomas have one of the highest cure rates of any malignancy, patients with primary refractory disease and disease which relapses early after initial therapy are difficult to cure. This project is focused on the development of Anti-CD30 antibodies as a radioimmunotherapeutic for the treatment of CD30+ lymphomas, primarily Hodgkin's Lymphoma. Radioimmunotherapy offers an attractive therapeutic option, administering targeted radiation to sites of disease. Hodgkin's Lymphoma is generally radiosensitive and radiation exerts its action in a non-cross resistant manner with combination chemotherapy. CD30, an antigen which was first defined on Hodgkin's Lymphoma is an attractive target for therapeutics and is currently being evaluated in trials with unmodified human antibodies, immunotoxins, and radioimmunotherapy. This proposal will focus on Radioimmunotherapy using optimal anti-CD30 constructs including appropriate radioisotopes for a potentially internalizing antigen system. HeFi-1 will be the antibody for the first clinical trial, using radio heavy metal conjugated material, 111/In for the imaging/dosimetry and 90y for the therapy. The antibody is already prepared for clinical studies and is supplied through a NCI-RAID grant. The combination of radiometal with HeFi-1 should prove optimal for therapy and will represent the first time an anti-CD30 antibody will be evaluated as a radioimmunotherapeutic with a radiometal. This is an important feature for an internalizing antigen system where the heavy metal will remain bound intracellularly, in distinction from iodinated antibodies where isotope is released on intracellular metabolism. Aim 2 will focus on the development of additional anti-CD30 antibody constructs, evaluating Ki-4 antibody which binds to a different CD30 cluster, as well as comparing three therapeutic isotopes, 131/I,90y, 67Cu. Ki-4 has been used in clinical trials in Germany and a cell bank has been transferred to COH for further development. Aim 3 will evaluate a series of anti-CD30 antibodies directed at the various epitopes of CD30 as carriers of radioisotopes and explore the potential of combining two or more antibodies for optimal internalization of the radioligand. The potential of controlling the shedding of CD30 from the surface of the tumor cells with metalloproteinase inhibitors will also be explored. Aim 4 will focus on the molecular engineering of the most promising anti-CD30 antibody as an optimal radioimmunotherapeutic exploring the scFv dimers(diabody) as well as minibody format.